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Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern

Author

Listed:
  • Inga Pfeffer

    (University of Oxford)

  • Lennart Brewitz

    (University of Oxford)

  • Tobias Krojer

    (University of Oxford)

  • Sacha A. Jensen

    (University of Oxford)

  • Grazyna T. Kochan

    (University of Oxford)

  • Nadia J. Kershaw

    (University of Oxford)

  • Kirsty S. Hewitson

    (University of Oxford)

  • Luke A. McNeill

    (University of Oxford)

  • Holger Kramer

    (University of Oxford)

  • Martin Münzel

    (University of Oxford)

  • Richard J. Hopkinson

    (University of Oxford)

  • Udo Oppermann

    (University of Oxford
    University of Oxford)

  • Penny A. Handford

    (University of Oxford)

  • Michael A. McDonough

    (University of Oxford)

  • Christopher J. Schofield

    (University of Oxford)

Abstract

AspH is an endoplasmic reticulum (ER) membrane-anchored 2-oxoglutarate oxygenase whose C-terminal oxygenase and tetratricopeptide repeat (TPR) domains present in the ER lumen. AspH catalyses hydroxylation of asparaginyl- and aspartyl-residues in epidermal growth factor-like domains (EGFDs). Here we report crystal structures of human AspH, with and without substrate, that reveal substantial conformational changes of the oxygenase and TPR domains during substrate binding. Fe(II)-binding by AspH is unusual, employing only two Fe(II)-binding ligands (His679/His725). Most EGFD structures adopt an established fold with a conserved Cys1–3, 2–4, 5–6 disulfide bonding pattern; an unexpected Cys3–4 disulfide bonding pattern is observed in AspH-EGFD substrate complexes, the catalytic relevance of which is supported by studies involving stable cyclic peptide substrate analogues and by effects of Ca(II) ions on activity. The results have implications for EGFD disulfide pattern processing in the ER and will enable medicinal chemistry efforts targeting human 2OG oxygenases.

Suggested Citation

  • Inga Pfeffer & Lennart Brewitz & Tobias Krojer & Sacha A. Jensen & Grazyna T. Kochan & Nadia J. Kershaw & Kirsty S. Hewitson & Luke A. McNeill & Holger Kramer & Martin Münzel & Richard J. Hopkinson & , 2019. "Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12711-7
    DOI: 10.1038/s41467-019-12711-7
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    Cited by:

    1. Yu Nakashima & Lennart Brewitz & Anthony Tumber & Eidarus Salah & Christopher J. Schofield, 2021. "2-Oxoglutarate derivatives can selectively enhance or inhibit the activity of human oxygenases," Nature Communications, Nature, vol. 12(1), pages 1-17, December.

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